Projected t-SNE for batch correction

Motivation: Low-dimensional representations of high-dimensional data are routinely employed in biomedical research to visualize, interpret and communicate results from different pipelines. In this article, we propose a novel procedure to directly estimate t-SNE embeddings that are not driven by batch effects. Without correction, interesting structure in the data can be obscured by batch effects. The proposed algorithm can therefore significantly aid visualization of high-dimensional data. Results: The proposed methods are based on linear algebra and constrained optimization, leading to efficient algorithms and fast computation in many high-dimensional settings. Results on artificial single-cell transcription profiling data show that the proposed procedure successfully removes multiple batch effects from t-SNE embeddings, while retaining fundamental information on cell types. When applied to single-cell gene expression data to investigate mouse medulloblastoma, the proposed method successfully removes batches related with mice identifiers and the date of the experiment, while preserving clusters of oligodendrocytes, astrocytes, and endothelial cells and microglia, which are expected to lie in the stroma within or adjacent to the tumours. Contact: [email protected]

Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression

Objectives Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP. Methods The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP. Results TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation. Conclusions The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments

Base de dados do Herbário IAN da Embrapa Amazônia Oriental.

Base de Dados do Herbário IAN da Embrapa Amazônia Oriental; Introdução; Histórico; Características da base de dados; Desenvolvimento; Segurança das informações; Usuários; Disponibilização na web.bitstream/item/94025/1/DOC-392.pd

Divided communities and contested landscapes: Mobility, development and shifting identities in migrant destination sites in Papua New Guinea

Internal conflicts at the local and national levels in several South Pacific countries have revealed the fragility of national unity and the difficulties nations face in governing and managing their own economic development. In Papua New Guinea, the focus of this paper, an uncertain economic future for many rural and urban communities, and rising inequalities in income opportunities and access to resources, have coincided with greater intolerance of migrants at sites of high in-migration by customary landowners and provincial and local authorities. This paper draws on fieldwork undertaken in the major oil palm growing regions of Papua New Guinea where migrants from densely populated regions of the country have settled on state land alienated from customary landowners. We examine how struggles over land, resource control and development are polarising migrant and landowner identities resulting in increasing tensions and episodic communal violence. A settler identity is emerging based on a narrative of nation building and national development, while an ethno-regional identity amongst customary landowners is undermining the citizen rights of migrants and challenging the role and authority of the state in land matters

An evaluation of primary care led dementia diagnostic services in Bristol

© 2014 Dodd et al. Background: Typically people who go to see their GP with a memory problem will be initially assessed and those patients who seem to be at risk will be referred onto a memory clinic. The demographic forces mean that memory services will need to expand to meet demand. An alternative may be to expand the role of primary care in dementia diagnosis and care. The aim of this study was to contrast patient, family member and professional experience of primary and secondary (usual) care led memory services. Methods: A qualitative, participatory study. A topic guide was developed by the peer and professional panels. Data were collected through peer led interviews of people with dementia, their family members and health professionals. Results: Eleven (21%) of the 53 GP practices in Bristol offered primary care led dementia services. Three professional panels were held and were attended by 9 professionals; nine carers but no patients were involved in the three peer panels. These panels identified four main themes: GPS rarely make independent dementia diagnosis; GPS and memory nurses work together; patients and carers generally experience a high quality diagnostic service; an absence of post diagnostic support. Evidence relating to these themes was collected through a total of 46 participants took part; 23 (50%) in primary care and 23 (50%) in the memory service. Conclusions: Patients and carers were generally satisfied with either primary or secondary care led approaches to dementia diagnosis. Their major concern, shared with many health care professionals, was a lack of post diagnostic support

Inflammation causes remodeling of mitochondrial cytochrome c oxidase mediated by the bifunctional gene C15orf48

Dysregulated mitochondrial function is a hallmark of immune-mediated inflammatory diseases. Cytochrome c oxidase (CcO), which mediates the rate-limiting step in mitochondrial respiration, is remodeled during development and in response to changes of oxygen availability, but there has been little study of CcO remodeling during inflammation. Here, we describe an elegant molecular switch mediated by the bifunctional transcript C15orf48, which orchestrates the substitution of the CcO subunit NDUFA4 by its paralog C15ORF48 in primary macrophages. Expression of C15orf48 is a conserved response to inflammatory signals and occurs in many immune-related pathologies. In rheumatoid arthritis, C15orf48 mRNA is elevated in peripheral monocytes and proinflammatory synovial tissue macrophages, and its expression positively correlates with disease severity and declines in remission. C15orf48 is also expressed by pathogenic macrophages in severe coronavirus disease 2019 (COVID-19). Study of a rare metabolic disease syndrome provides evidence that loss of the NDUFA4 subunit supports proinflammatory macrophage functions